JPS5829318B2 - Prostaglandin Luijika Goubutsu Houhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing frostaglandin estradiol ester.

Prostaglandins (PGs) are present in each tissue of animals.
It is secreted in vivo and is known as a fat-soluble substance that affects smooth muscle, blood pressure, lipid metabolism, gastric acid secretion, platelet aggregation, etc. in minute amounts.

Therefore, prostaglandins are useful as antihypertensive diuretics, antithrombotic agents, bronchodilators, antiulcer agents, agents for promoting labor and abortion, and agents for preventing arteriosclerosis.

Natural frostaglandin has a basic skeleton represented by the formula, and the main five-membered ring structure includes a PGE group, a PGF group, and a PGA group, and the structure is as shown in the following formula.

Furthermore, depending on the position of the double bond, PG
-1 group (trans-△13), PG-2 group (cis-△5)
trans-Δ13) and PG-3 groups (cis-Δ5, trans-Δ13, cis-Δ17).

Various PGs produced by differences in the ring structure or the position of the double bond each exhibit specific pharmacological effects.

Various glostaglan esters produced by nitrifying the carboxyl group of prostaglandin with alcohols having various structures have specific pharmacological effects such as enhancement of blood pressure lowering effect or prolongation of the duration of blood pressure lowering effect. It is known that

We have now completed the present invention by discovering that β-estradiol ester of prostaglandin F has a strong implantation inhibiting effect and a luteal regression effect.

That is, when PGF2C1-β-estradiol ester, one of the products of the present invention, was subcutaneously injected into pregnant rats at 0.5 μ/ky for 3 days on days 3, 4, and 5, it had a significant implantation inhibiting effect. The potency was approximately 4 times that of PGF2C1.

According to the present invention, prostaglandins represented by the general formula (R is a linear or branched alkyl group having 1 to 10 carbon atoms, and ~OH represents α, β, or a mixture of both) As a tertiary amine salt,
React with pivaloyl halide to form a mixed acid anhydride.

By reacting this with β-estradiol,
Estradiol esters of prostaglandins represented by the general formula (R and ~~OH represent the same meanings as above) can be synthesized.

A method for synthesizing prostaglandin ester using a mixed acid anhydride of prostaglandin and pivaloyl acid has already been filed by the present inventors (Japanese Patent Publication No. 49-20766
issue).

In this application, a large excess of alcohol is always used to react the mixed acid anhydride, but this method cannot be applied to β-estradiol because it is extremely expensive.

Initially, 1 equivalent of β-estradiol was reacted with the mixed acid anhydride, but it was difficult to obtain the desired product.

As a result of various studies, it was possible to obtain the desired product by using 3 to 6 equivalents of mixed acid anhydride to β-estradiol.

The reaction is carried out as follows.

Prostaglandin is dissolved without a solvent or in an inert organic solvent such as methylene chloride, ether, or chloroform, and preferably a tertiary amine such as triethylamine or pyridine is added while stirring under water cooling or at room temperature.

After a few minutes of adding pivaloyl halide, β-estradiol and then pyridine are added, and the mixture is stirred at room temperature for 12 to 18 hours.

In this case, the tertiary amine and pivaloyl halide are preferably used in an equivalent amount or slightly in excess of the prostaglandin.

β-estradiol is preferably used in a molar amount of 10 to more times that of prostaglandin.

After the reaction is completed, the residue is purified by washing with water and distilling off the solvent under reduced pressure using a silica gel column.

Next, examples will be shown.

Example Synthesis of prostaglandin F2 (X β-estradiol) 651 mI of prostaglandin F2a was dissolved in 10 ml of tetrahydrofuran, 175 ml of pyridine was added, and the mixture was cooled on ice in a nitrogen stream.

267 m9 of pivaloyl chloride dissolved in 1 ml of tetrahydrofuran was added thereto, and the mixture was warmed to room temperature and stirred for 40 minutes.

43.5 ml of pyridine was added to the reaction mixture, and the mixture was cooled to 0°C. 100 ml of 17(J3)-estradiol dissolved in 5 rrL of tetrahydrone was added dropwise, and the mixture was warmed to room temperature again and stirred for 18 hours.

The solvent was distilled off under reduced pressure, and 30 TrL of ethyl acetate was added to the residue to separate out the precipitated crystals of pyridine hydrochloride.

The first solution was washed with an aqueous oxalic acid solution, washed with water to make it neutral, dried and concentrated under reduced pressure to obtain a crude product 7oomy.

Next, this was used as an elution solvent in a silica gel column: ■cyclohexane:ethyl acetate (1:1), ■chloroform:
Purification was carried out three times using tetrahydrofuran (8:1), the same as in ■ and ■, to obtain the title substance 24■ as an oil.

Thin layer chromatography (chloroform:tetrahydrofuran:acetic acid-10:2:1): Rf=0.25 Infrared absorption spectrum (liquid film method): 3350.2930.
2860.1750.16101430,. 1220
1160 1140.975CrrL' Nuclear magnetic resonance spectrum (deuterated chloroform solution): δ-7
, 27 (LH1 doublet), 6.80 (IH.

double line), 6.77 (IH, - double line), 5.58-5.
35 (4H1 multiplet), 4.21-3.56 (4H1 multiplet), 2.96-1.05 (39H1 multiplet).

Claims (1)

[Scope of Claims] (R is a linear or branched alkyl group having 1 to 10 carbon atoms, and -OH is at the α-position, β-position, or a mixture of both.) gin as a tertiary amine salt,
A prosthetic compound represented by the general formula (tan and ~~OH have the same meanings as above) characterized by reacting pivaloyl halogenide to form a mixed acid anhydride and reacting this with β-estradiol. A method for producing β-estradiol ester of grandin.